Longitudinal assessment of lung clearance index to monitor disease progression in children and adults with cystic fibrosis

BackgroundLung clearance index (LCI) is a valuable research tool in cystic fibrosis (CF) but clinical application has been limited by technical challenges and uncertainty about how to interpret longitudinal change. In order to help inform clinical practice, this study aimed to assess feasibility, repeatability and longitudinal LCI change in children and adults with CF with predominantly mild baseline disease.MethodsProspective, 3-year, multicentre, observational study of repeated LCI measurement at time of clinical review in patients with CF >5 years, delivered using a rapid wash-in system.Results112 patients completed at least one LCI assessment and 98 (90%) were still under follow-up at study end. The median (IQR) age was 14.7 (8.6–22.2) years and the mean (SD) FEV1 z-score was −1.2 (1.3). Of 81 subjects with normal FEV1 (>−2 z-scores), 63% had raised LCI (indicating worse lung function). For repeat stable measurements within 6 months, the mean (limits of agreement) change in LCI was 0.9% (−18.8% to 20.7%). A latent class growth model analysis identified four discrete clusters with high accuracy, differentiated by baseline LCI and FEV1. Baseline LCI was the strongest factor associated with longitudinal change. The median total test time was under 19 min.ConclusionsMost patients with CF with well-preserved lung function show stable LCI over time. Cluster behaviours can be identified and baseline LCI is a risk factor for future progression. These results support the use of LCI in clinical practice in identifying patients at risk of lung function decline.

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Faculty Opinions recommendation of Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10232957.11024056 ◽

2011 ◽

Author(s):

Michael Schechter ◽

Pravin K Sah

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Lung Clearance ◽

Lung Clearance Index

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P212 Ventilation MRI tracks longitudinal lung function changes in patients with cystic fibrosis and clinically stable FEV1 and Lung Clearance Index

Journal of Cystic Fibrosis ◽

10.1016/s1569-1993(19)30505-3 ◽

2019 ◽

Vol 18 ◽

pp. S117

Author(s):

L. Smith ◽

G. Collier ◽

H. Marshall ◽

P. Hughes ◽

A. Biancardi ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Lung Clearance ◽

Lung Clearance Index

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Elevated lung clearance index in infants with cystic fibrosis shortly after birth

European Respiratory Journal ◽

10.1183/13993003.00580-2017 ◽

2017 ◽

Vol 50 (5) ◽

pp. 1700580 ◽

Cited By ~ 10

Author(s):

Elisabeth Kieninger ◽

Sophie Yammine ◽

Insa Korten ◽

Pinelopi Anagnostopoulou ◽

Florian Singer ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Specific Treatment ◽

Lung Clearance ◽

Time To Peak ◽

Ventilation Inhomogeneity ◽

Lung Clearance Index ◽

Residual Capacity ◽

Z Scores ◽

Noninvasive Markers

It is not known at what age lung function impairment may arise in children with cystic fibrosis (CF). We assessed lung function shortly after birth in infants with CF diagnosed by newborn screening.We performed infant lung function measurements in a prospective cohort of infants with CF and healthy controls. We assessed lung clearance index (LCI), functional residual capacity (FRC) and tidal breathing parameters. The primary outcome was prevalence and severity of abnormal lung function (±1.64 z-scores) in CF.We enrolled 53 infants with CF (mean age 7.8 weeks) and 57 controls (mean age 5.2 weeks). Compared to controls, LCI and FRC were elevated (mean difference 0.30, 95% CI 0.02–0.60; p=0.034 and 14.5 mL, 95% CI 7.7–21.3 mL; p<0.001, respectively), while ratio of time to peak tidal expiratory flow to expiratory time was decreased in infants with CF. In 22 (41.5%) infants with CF, either LCI or FRC exceeded 1.64 z-scores; three infants had both elevated LCI and FRC.Shortly after birth, abnormal lung function is prevalent in CF infants. Ventilation inhomogeneity or hyperinflation may serve as noninvasive markers to monitor CF lung disease and specific treatment effects, and could thus be used as outcome parameters for future intervention studies in this age group.

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An 8 week open-label interventional multicenter study to evaluate the lung clearance index as endpoint for clinical trials in cystic fibrosis patients ≥8 years of age, chronically infected with Pseudomonas aeruginosa

10.21203/rs.3.rs-15870/v2 ◽

2020 ◽

Author(s):

Sivagurunathan Sutharsan ◽

Susanne Naehrig ◽

Uwe Mellies ◽

Christian Sieder ◽

joerg Zeigler

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Lung Function ◽

Lung Disease ◽

Small Airways ◽

Open Label ◽

Lung Clearance ◽

Efficacy Trials ◽

Inhaled Antibiotics ◽

Lung Clearance Index

Abstract Background Forced expiratory volume in 1 second (FEV 1 ) is the only parameter currently recognized as a surrogate endpoint in cystic fibrosis (CF) trials. However, FEV 1 is relatively insensitive to changes in the small airways of patients with milder lung disease. This pilot study aimed to evaluate the lung clearance index (LCI) as a marker for use in efficacy trials with inhaled antibiotics in CF. Methods This open-label, single-arm study enrolled CF patients with Pseudomonas aeruginosa infection, who were treated with tobramycin (28-day on/off regime). FEV 1 , LCI and bacterial load in sputum (CFU) were assessed at baseline, after 1, 4 and 8 weeks of treatment. Results All patients (n=17) showed elevated LCI of >11 despite 3 patients having normal FEV 1 (>90% predicted) at baseline. Overall, LCI improved in 8 (47%) patients and FEV 1 in 9 (53%) patients. At week 4, LCI improved by 0.88, FEV 1 increased by 0.52%, and P. aeruginosa reduced by 30481.3 CFU/mL. These changes were however statistically non-significant. Six adverse events occurred in 5/17 (29.4%) patients, most of which were mild-to-moderate in severity. Conclusions Due to the low evaluable sample size, no specific trend was observed related to the changes between LCI, FEV1 and CFU. Based on the individual data from this study and from recently published literature, LCI has been shown to be a more sensitive parameter than FEV1 for lung function. LCI can hypothesized to be an appropriate endpoint for efficacy trials in CF patients if the heterogeneity in lung function is limited by enrolling younger patients or patients with more milder lung disease and thus, limiting the ventilation inhomogeneities. Trial registration : The study is registered with ClinicalTrials.gov, identifier: NCT02248922

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Association of lung clearance index with survival in individuals with cystic fibrosis

European Respiratory Journal ◽

10.1183/13993003.00432-2021 ◽

2021 ◽

pp. 2100432

Author(s):

Johanna Manuela Kurz ◽

Kathryn Angela Ramsey ◽

Romy Rodriguez ◽

Ben Spycher ◽

Reta Fischer Biner ◽

...

Keyword(s):

Cystic Fibrosis ◽

Sensitivity Analyses ◽

Event Analysis ◽

Z Score ◽

Lung Clearance ◽

Risk Of Death ◽

Ventilation Inhomogeneity ◽

Hazard Ratios ◽

Lung Clearance Index ◽

The Mean

BackgroundThe lung clearance index (LCI) assesses global ventilation inhomogeneity and is a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease.ObjectivesWe examined the association of LCI with the risk of death or lung transplantation (LTX) in individuals with CF.MethodsWe performed a retrospective analysis in a cohort of individuals with CF aged≥5 years with LCI and FEV1 measurements performed between 1980 and 2006. The outcome was time until death or LTX. We used the earliest available LCI and FEV1 values in a Cox proportional hazard regression adjusted for demographic and clinical variables. For sensitivity analyses, we used the mean of the first three LCI and FEV1 measurements, stratified the cohort based on age, and investigated individuals with normal FEV1.ResultsIn total, 237 individuals with CF with a mean (range) age of 13.9 (5.6–41.0) years were included. The time-to-event analysis accrued 3813 person-years and 94 (40%) individuals died or received LTX. Crude hazard ratios [95% CI] were 1.04 [1.01–1.06] per one z-score increase in LCI and 1.25 [1.11–1.41] per one z-score decrease in FEV1. After adjusting LCI and FEV1 mutually in addition to sex, age, BMI and the number of hospitalisations, hazard ratios were 1.04 [1.01–1.07] for LCI, and 1.12 [0.95–1.33] for FEV1. Sensitivity analyses yielded similar results and using the mean LCI strengthened the associations.ConclusionsIncreased ventilation inhomogeneity is associated with greater risk of death or LTX. Our data support LCI as novel surrogate of survival in individuals with CF.

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